Abstract 9921: Angiotensin II Receptor Blocker Improves Exercise Capacity and Mitochondrial Function of Skeletal Muscle via Inhibiting Oxidative Stress in High Fat Diet-Induced Diabetic Mice

Background We have previously reported that the exercise capacity is reduced and mitochondrial function is impaired in high fat diet (HFD)-induced diabetic mice, which is due to NAD(P)H oxidase-induced oxidative stress. NAD(P)H oxidase can be activated by angiotensin II. Hypothesis We thus hypothesized that angiotensin II receptor blocker can ameliorate the reduced exercise capacity in diabetic mice. Methods C57BL/6J mice were fed on normal diet (ND) or HFD, and each group of mice was divided into 2 groups of the treatment with or without olmesartan (OLM, 3mg/kg/day) in the drinking water. Four groups of mice, ND (n=10), ND+OLM (n=10), HFD (n=15), and HFD+OLM (n=15), were studied. After 8 weeks, treadmill tests were performed to determine the work and oxygen uptake (VO 2 ). ADP-dependent (state 3) respiration in mitochondria was determined, and NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence method were measured in isolated skeletal muscle. Results HFD significantly increased body weight, adipose tissue weight, plasma glucose and insulin compared to ND, and OLM did not affect these parameters in either group. The work and peak VO 2 were significantly reduced in HFD compared to ND (work; 14±1 vs 28±2 J, peak VO 2 ; 111±2 vs 145±3 mL/kg/min), and these reductions were ameliorated in HFD+OLM (work; 18±1 J, peak VO 2 ; 122±3 mL/kg/min). State 3 respiration was significantly decreased, and NAD(P)H oxidase activity and superoxide production were significantly increased in HFD compared with ND (state 3 respiration; 58±3 vs 39±3 nmol/min/mg protein, NAD(P)H oxidase activity; 403±70 vs 1771±326 RLU/min/100µg protein, superoxide; 61±11 vs 181±27 RLU/min/mg), which was attenuated by OLM (state 3 respiration; 56±3 nmol/min/mg protein, NAD(P)H oxidase activity; 646±51 RLU/min/100µg protein, superoxide; 81±20 RLU/min/mg). There were no such effects by OLM in ND mice. Conclusions Olmesartan ameliorated the reduced aerobic capacity in HFD-induced diabetic mice via the improvement of impaired mitochondrial function and attenuation of oxidative stress in the skeletal muscle. The improvement of aerobic capacity by angiotensin II receptor blocker may have a clinical impact in the treatment of patients with diabetes mellitus.